Methods of colchicine administration

ABSTRACT

The invention provides improved methods for coadministration of colchicine with drugs metabolized by CYP3A4 (anciently referred to as cytochrome P450 isozyme 3A4) or the P-glycoprotein transporter, but not both. The method enables non-toxic coadministration of colchicine and the second drug at their ordinary levels safely and effectively without reducing the dose or frequency for either drug.

FIELD OF THE INVENTION

This invention relates to methods of administering colchicine for thetreatment of inflammatory disorders such as chronic gout, particularlyto dosing of colchicine when coadministered with other drugs that sharecommon metabolic pathways, for improved safety and efficacy.

BACKGROUND

Gout, also called gouty arthritis, is a painful inflammatory disorderthat arises when uric acid accretes in the joints because it is eitheroverproduced or the kidneys cannot excrete enough. Gout typicallymanifests as a flare: a sudden, unpredictable and excruciating burningpain with redness, swelling, warmth and stiffness of the joint,sometimes with low fever. The lower extremities and especially the bigtoe are commonly affected. Gout is an effect of rich diets and isincreasingly common: it affects 1-2% of the Western population at somepoint in their lifetimes.

Colchicine has been used to treat gout for centuries. Colchicine is alsothe drug of choice for several other debilitating inflammatorydisorders, including familial Mediterranean fever, pericarditis,Behçet's disease, immunosuppression, chronic constipation, and otherconditions. Colchicine's potential as an anticancer drug is also underinvestigation.

Colchicine is a tricyclic alkaloid (C22H25NO6; formula weight 399.4)that is present in Colchicum autumnale and Gloriosa superba as well asother plants. Its chemical structure is depicted below:

The formal name of the molecule is(S)N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[alpha]heptalen-7-yl)acetamide.Colchicine is now used to prevent acute flares for chronic gout patientsin most parts of the world.

Colchicine's mechanism of action has not yet been fully elucidated butthe following is known. Colchicine decreases the inflammatory responseto urate crystal deposition by impairing the motility of granularleukocytes. Colchicine also interferes with urate deposition bydecreasing lactic acid production by leukocytes. Colchicine alsointerferes with kinin formation, diminishes phagocytosis and subsequentinflammatory responses, and disrupts microtubules. It also inhibitsmitosis, thereby especially affecting cells that have high turnoverrates such as in the gastrointestinal tract and bone marrow. Nausea anddiarrhea are the primary adverse side effects of colchicine therapy whenit is used in a safe dosage range.

Typically Colchicine is administered orally and is rapidly absorbedthrough the gastrointestinal tract. In patients with normal organfunction, peak concentrations in the blood are reached within about 2hours. Colchicine and its metabolites (mainly 3-demethylcolchicine and2-demethylcolchicine) distribute to the white blood cells, livermicrosomes, kidneys, spleen and intestines. The liver metabolizescolchicine. The compound and/or its metabolites are excreted in fecesbut up to 20% of colchicine passes unchanged in the urine.

The margin of safety for colchicine doses is narrow, posing a specialrisk from drug-drug interactions that have the effect of increasingcolchicine concentrations in the blood by slowing its metabolism orother elimination. Rhabdomyolysis and in many cases death have beenreported when colchicine levels in the blood substantially exceededclinically recommended levels, particularly in patients who had impairedfunction of the liver or kidneys.

In individuals whose organ function is impaired colchicine can persistin the body at very high (i.e., toxic) levels for long periods. Moreovera large number of physicians have reported that drug-drug interactionsresult in sustained toxic levels of colchicine even in patients whoseorgan function was normal. Two physiological processes require specialconsideration to maintain colchicine in a safe range in the blood.Firstly, the body's main drug metabolic enzymes for colchicine are fromthe CYP3A subfamily, especially CYP3A4 present in the liver,gastrointestinal tract, kidney and other sites. The medical consensus isthat when a coadministered drug inhibits CYP3A4 activity, colchicine'shalf-life and bioavailability is greatly increased and toxicity is muchmore likely if the dose of colchicine is not reduced.

Secondly, P-glycoprotein (P-gp) acts as an efflux pump to evict manyxenobiotics—including colchicine—from the inside to the outside of cellsin an ATP-dependent way. P-gp is encoded by the multiple drug resistance1 gene (MDR1), known as the ATP-binding cassette subfamily B member 1(ABCB1) gene. Medical consensus is that when a coadministered druginhibits P-gp activity, colchicine's bioavailability should increasebecause of inhibition of P-gp in the gut, and its half life in the bloodmay increase because if inhibition of P-gp in the kidney, therebyincreasing the likelihood of toxicity.

Numerous articles have suggested that CYP3A4 and P-gp act in concertwith one another and are inhibited by many of the same agents. (Z. Yanget al., J. Pharmacol. Exp. Ther. 2008; 327:474-81; S. Choudhuri and K.D. Claassen, Int. J. Toxicol. 2006; 25:231-59; S. Zhou et al., DrugMetab. Res. 2004; 36:57-104; F. Thiebaut et al., Proc. Natl. Acad. Sci.USA 1987; 84:7735-8; I. Sugawara et al., Cancer Res. 1988; 48:1926-9; V.J. Wacher et al., Mol. Carcinog. 1995; 13:129-34; C. Wandel et al.,Cancer Res. 199; 59:3944-8.) As a consequence, physicians are typicallyadvised not to coadminister any second drug with colchicine if thesecond drug is known to inhibit either CYP3A4 or P-gp. At a minimum,physicians are encouraged to reduce the dose of colchicine to minimizethe risk of toxicity, even though this reduction might lower the dosebeyond a therapeutically effective amount.

A leading clinical study on coadministration of CYP3A4 inhibitors withcolchicine recommends colchicine's dosage be lower to less than thestandard dose (i.e., lower than the dose used when no inhibitor iscoadministered) by about 33-75%, and further recommends thatadministration at the low dosage should be only one half or one third asoften as the standard frequency, all to be determined as a function ofthe strength of inhibition. (R. A. Terkeltaub et al., “Novelevidence-based colchicine dose-reduction algorithm to predict andprevent colchicine toxicity in the presence of cytochrome P4503A4/P-glycloprotein inhibitors,” Arthritis and Rheumatism, 2011;63:2226-2237, 3521). In other words, those authors found that in theaggregate, the total amount of colchicine that may be tolerable overtime is as little as one tenth of the total for the standard dose.Unfortunately the adjusted doses of Terkeltaub et al. require anenhanced level of monitoring because the margin for error is smallespecially for chronic administration.

The FDA has warned that indiscriminate administration of colchicine withCYP3A4 inhibitors or P-gp inhibitors can create life-threateningconditions and an increased number of serious adverse events. (Food andDrug Administration, “Information for healthcare professionals: newsafety information for colchicine (marketed as Colcrys); 2009. URL:http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm174382.htm).Unfortunately the constraints on coadministration are particularlysevere for gout patients. These individuals are commonly afflicted byobesity, hypertension, heart disease, systemic infections, depressionand other conditions. Yet the drugs to be avoided due to the inhibitioninteractions with CYP3A4 or P-gp are often the most preferred fortreating those secondary conditions. Hence the patient need is urgentand ongoing for a method of treatment that provides colchicineconveniently in safe and effective amounts while simultaneously enablingconcomitant administration of second drugs that happen to inhibit CYP3A4or P-gp.

SUMMARY OF THE INVENTION

Whereas the prior art teaches that reductions in colchicine dosing areneeded whenever a CYP3A4 inhibitor or P-gp substrate are co-administeredwith colchicine, the inventors have discovered that several drugs thatinhibit only one of CYP3A4 and P-gp but not the other can becoadministered with colchicine without any colchicine dosing reduction.Patients on chronic long-term therapy with colchicine no longer needworry when they must start taking one of these potentially interactingdrugs. In addition, they need not suffer drops in colchicine efficacydue to unnecessary and inadvisable dosing reductions.

Therefore, in a first embodiment the invention provides a method ofchronically treating a patient for an inflammatory disorder withcolchicine while concomitantly administering a second drug that is aninhibitor of CYP3A4 but is not an inhibitor for P-gp, wherein the methodcomprises:

-   -   a) administering to the patient a therapeutically effective        fixed maintenance dose of colchicine in an amount of from about        0.6 to about 1.2 mg/day, for a maintenance period of a plurality        of days;    -   b) before or after step (a), administering to the patient one or        more therapeutically effective doses of the second drug; and    -   c) concomitantly with step (b), administering to the patient the        fixed maintenance dose of colchicine of step (a) without dose        reduction.        In various embodiments, a strong inhibitor of CYP3A4 such as        voriconazole, a moderate inhibitor such as fluconazole, or a        weak inhibitor such as propafenone, administered in conventional        therapeutically effective doses.

In a second embodiment the invention provides a method of chronicallytreating a patient for an inflammatory disorder while concomitantlyadministering a second drug that is an inhibitor of P-gp but is not aninhibitor for CYP3A4, wherein the method comprises:

-   -   a) administering to the patient a therapeutically effective        fixed maintenance dose of colchicine in an amount of from about        0.6 to about 1.2 mg/day, for a maintenance period of a plurality        of days;    -   b) before or after step (a), administering to the patient one or        more therapeutically effective doses of the second drug; and    -   c) concomitantly with step (b), administering to the patient the        fixed maintenance dose of colchicine of step (a) without dose        reduction.        In one embodiment the P-gp inhibitor is propafenone,        administered in a conventional therapeutically effective dose.

Additional embodiments and advantages of the invention will be set forthin part in the description which follows, and in part will be obviousfrom the description, or may be learned by practice of the invention.The embodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims. It is to be understood that both theforegoing general description and the following detailed description areexemplary and explanatory only and are not restrictive of the invention,as claimed.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the linear profile of the mean plasma concentrationof colchicine (CLN) in coadministration with voriconazole (VCZ).

FIG. 2 is a graph of the logarithmic profile of the mean plasmaconcentration of colchicine (CLN) in coadministration with voriconazole(VCZ).

FIG. 3 is a graph of the linear profile of the mean plasma concentrationof colchicine (CLN) in coadministration with fluconazole (FCZ).

FIG. 4 is a graph of the logarithmic profile of the mean plasmaconcentration of colchicine (CLN) in coadministration with fluconazole(FCZ).

FIG. 5 is a graph of the linear profile of the mean plasma concentrationof colchicine (CLN) in coadministration with cimetidine (CMN).

FIG. 6 is a graph of the logarithmic profile of the mean plasmaconcentration of colchicine (CLN) in coadministration with cimetidine(CMN).

FIG. 7 is a graph of the linear profile of the mean plasma concentrationof colchicine (CLN) in coadministration with propafenone (PFN).

FIG. 8 is a graph of the logarithmic profile of the mean plasmaconcentration of colchicine (CLN) in coadministration with propafenone(PFN).

DETAILED DESCRIPTION OF THE INVENTION

The invention may be more fully understood by reference to the followingdefinitions.

When the singular forms “a,” “an” and “the” or like terms are usedherein, they will be understood to include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “apharmaceutical carrier” includes mixtures of two or more such carriers,and the like. The word “or” and like terms mean any one member of aparticular list and also includes any combination of members of thatlist.

When used herein the term “about” or “ca.” will compensate forvariability allowed for in the pharmaceutical industry and inherent inpharmaceutical products, such as differences in product strength andbioavailability due to manufacturing variations and time-induced productdegradation. The term allows for any variation which in the practice ofpharmaceuticals would allow the product being evaluated to be consideredpharmaceutically equivalent or bioequivalent, or both if the contextrequires, to the recited strength of a claimed product.

Throughout the description and claims of this specification, the word“comprise” and variations of the word, such as “comprising” and“comprises,” means “including but not limited to,” and is not intendedto exclude, for example, other additives, components, integers or steps.

The term “inflammatory disorder” refers to an inflammatory disorder thatresponds to treatment by colchicine: these include but are not limitedto gout (acute or chronic), familial Mediterranean fever (FMF);pericarditis; Behçet's disease; constipation-predominant irritable bowelsyndrome; and aphthous stomatitis (canker sores).

The term “flare” refers to an acute attack of a recurring nature.

The terms “acute” and “chronic” have their usual and ordinary meaning inthe medical arts, both with respect to the duration, persistence andrecurrence of a patient's medical condition and with respect to theduration of treatment.

The terms “treating” and “treatment,” when used herein, refer to themedical management of a patient with the intent to cure, ameliorate,stabilize, or prevent a disease, pathological condition, or disorder.This term includes active treatment, that is, treatment directedspecifically toward the improvement of a disease, pathologicalcondition, or disorder, and also includes causal treatment, that is,treatment directed toward removal of the cause of the associateddisease, pathological condition, or disorder. In addition, this termincludes palliative treatment, that is, treatment designed for therelief of symptoms rather than the curing of the disease, pathologicalcondition, or disorder; preventative treatment, that is, treatmentdirected to minimizing or partially or completely inhibiting thedevelopment of the associated disease, pathological condition, ordisorder; and supportive treatment, that is, treatment employed tosupplement another specific therapy directed toward the improvement ofthe associated disease, pathological condition, or disorder.

The terms “administer” and “administration” have their usual andordinary meaning in the art of treating a patient with a drug. The terms“coadministration” and “concomitant administration” as used herein aresynonymous and refer to administering two drugs to a patient in such amanner and with such timing that both drugs reside in the patient's bodyat the same time. The coadministration may be simultaneous or sequentialin time, and the coadministered drugs may be administered to a patientat the same time, or separately but near in time, or on the same day, orotherwise in a way that results in substantial overlap of the residenceperiods for the respective drugs in the body.

The term “maintenance dose” refers to a dose at which colchicine isadministered at a fixed dose for a sustained period of time. The term“maintenance period” refers to the duration of time over whichmaintenance doses are provided; this typically is at least sevenconsecutive days and may be much longer. The term “fixed” as used withrespect to a dose refers to an amount that is relatively constant fromone administration episode to the next. The term “therapeuticallyeffective” refers to a dose that is considered sufficient to cause asatisfactory positive improvement in the medical condition beingtreated, when administered according to the prescribed course oftreatment. With respect to colchicine a particularly preferred range forfixed maintenance doses is an amount of from 0.6 mg/day to about 1.2mg/day but the invention is not so limited, and can range from 0.3 or0.6 mg/day to 1.8 or 2.4 mg/day.

With respect to voriconazole a preferred therapeutically effective oraldose is from about 100 or 200 mg/day to about 400, 600 or 800 mg/day butthe invention is not so limited. With respect to fluconazole aparticularly preferred therapeutically effective oral dose is from about50, 100, or 200 mg/day to about 400 mg/day but the invention is not solimited. With respect to cimetidine a particularly preferredtherapeutically effective oral dose is from about 200, 400, 600 or 800mg/day to about 1,200, 1,600, or 2,000 mg/day but the invention is notso limited. With respect to propafenone a particularly preferredtherapeutically effective oral dose is from about 300 or 450 mg/day toabout 675 or 900 mg/day but the invention is not so limited.

In any of the foregoing embodiments, the potentially interacting drugcan be administered as the free base or a pharmaceutically acceptablesalt thereof.

“Pharmaceutically acceptable salts” means salts that arepharmaceutically acceptable, as defined below, and that possess thedesired pharmacological activity. Such salts include acid addition saltsformed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or withorganic acids such as acetic acid, propionic acid, hexanoic acid,heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acidp-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like.

In addition, pharmaceutically acceptable salts may be formed when anacidic proton present is capable of reacting with inorganic or organicbases. Acceptable inorganic bases include sodium hydroxide, sodiumcarbonate, potassium hydroxide, aluminum hydroxide and calciumhydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

The term CYP (previously known as “cytochrome P450”) refers to theliver's family of metabolic enzymes, as are known to practitioners ofthe art. The terms CYP3A and CYP3A4 refer to a subfamily of enzymes andto a particular enzyme, respectively.

The term “P-glycoprotein” (P-gp) refers to the protein encoded by themultiple drug resistance 1 gene (MDR1), which gene is also known as theATP-binding cassette subfamily B member 1 (ABCB1) gene. P-gp is to beunderstood here as an ATP-dependent pump for transporting drug moleculesout of cell interiors.

The terms “inhibitor”, “inducer”, “substrate”, “enzyme”, “isozyme” (thelatter being synonymous with “isoenzyme”), and “molecular pump” havetheir usual and ordinary meaning in biochemistry for describing theeffects of drug molecules on the activity of enzymes and moleculartransport proteins in human bodies, but with the followingqualifications. The term inhibitor as used herein includes bothcompounds that prevent binding of another molecule to an enzyme ormolecular pump and compounds that cause downregulation of the enzyme ormolecular pump. Similarly the term inducer as used herein includes bothcompounds that facilitate binding of another molecule to an enzyme ormolecular pump and compounds that cause upregulation of the enzyme ormolecular pump. The FDA's definition is used here for the relativestrength of CYP3A4 inhibitors regarding their effect on a CYP3A4substrate drug with which the respective inhibitor is coadministered.“Strong inhibitors” cause ≧5-fold (i.e., 400%) increase in AUC (areaunder curve over time for substrate drug concentration in the blood) or≧80% decrease in oral clearance rate. “Moderate inhibitors” cause≧2-fold but <5-fold (i.e., 100-399%) increase in AUC or 50-80% decreasein oral clearance rate. “Weak inhibitors” cause ≧1.25-fold but <2-fold(i.e., 25-99%) increase in AUC or 20-50% decrease in oral clearancerate. Likewise the FDA's definition is used here for the relativestrength of P-gp inhibitors: the FDA classifies drugs as being merelyinhibitors (i.e., causing ≧25% increase in AUC of a substrate compound)or non-inhibitors. (See Tables 4, 5, and 14 and their respective headersand notes athttp://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.Htm#potency).

Lists of inhibitors, inducers and substrates for CYP3A4 and P-gp canalso be found, for instance, athttp://www.pharmacologyweekly.com/content/pages/online-drug-therapy-tables,http://youscript.com/P-gp-table/, http://www.edhayes.com/CYP450-2.html,http://www.genemedrx.com/Cytochrome_P450_Metabolism_Table.php, and othersites.

The term “dual inhibitor” as used herein refers to a compound thatinhibits both CYP3A4 and P-gp in the human body. Examples of dualinhibitors include but are not limited to amiodarone, biricodar,bocepravir, clarithromycin, cyclosporine, darunavir, diltiazem,dronedarone, erythromycin, fenofibrate, fluoxetine/norfluoxetine,fluvoxamine, grapefruit juice (and its bergamottin content),itraconazole, josamycin, ketoconazole, lovastatin, metronidazole,mibefradil, mifepristone, nefazodone, nicardipine, nifedipine, piperine,posaconazole, quercetin, quinine, ritonavir, saquinavir, tacrolimus,telaprevir, telithromycin, and verapamil.

The term “single inhibitor” as used herein refers to a compound thatinhibits one of CYP3A4 or P-gp in the human body but not both. Examplesof single inhibitor compounds that inhibit CYP3A4 but not P-gp includebut are not limited to aprepitant, buprenorphine, cafestol,chloramphenicol, cimetidine, ciprofloxacin, danazol, delavirdine,fluconazole, imatinib, midazolam, norfloxacin, and voriconazole, as wellas extracts from the following botanical species Allium sativum, Ammivisnaga, Azadirachta indica, Cimicifuga racemosa, Harpagphytumprocumbens, Hydrastis Canadensis, naringenin compounds (e.g., fromgrapefruit), Panax ginseng, Panax quinquefolius, Strychnos ligustrinaand Uncaria tomentos. Examples of single inhibitor compounds thatinhibit P-gp but not CYP3A4 include but are not limited to alfentanil,amitripyline, astemizole, atorvastatin, azelastine, bepidil,bromocriptine, carbamazepine, carvedilol, chloroquine, chlorpromazine,digoxin, disulfiram, doxazosin, elacridar, emetine, felodipine,fentanyl, FK506, fluphenazine, gallopamil, garlic extract, haloperidol,imipramine, ivermectin, lidocaine, loratadine, methadone, nobilitin,norverapamil, progesterone, propafenone, propranolol, quinidine,reserpine, simvastatin, terfenadine, valinomycin, valspodar andvinblastine.

The terms “mean”, “geometric mean”, “least squares means” (LSmeans),“confidence limits” (CI, expressed in units of %), and “coefficient ofvariation” (C.V., expressed in units of %), have their usual andordinary meaning for clinical statistics and are well known topractitioners of the pharmaceutical arts in descriptors ofpharmacokinetic parameters.

The term “C_(max)” (expressed in units of pg/mL) means maximum observedplasma concentration and refers herein to that of colchicine. The term“ln(C_(max))” means the natural logarithm of the numerical value ofC_(max).

The term “T_(max)” (expressed in units of hours, or as a median numberof hours for T_(max) in the study population) means the observed time toreach C_(max) following drug administration; if it occurs at more thanone time point T_(max) is defined as the first time point with thisvalue.

The term “AUC_(T)” (expressed in units of pg·h/mL) means the cumulativearea under the plasma time concentration curve (AUC) calculated usingthe trapezoidal method from time 0 to the time of the last observedquantifiable plasma concentration (T_(LQC)). The term “ln(AUC_(T))”means the natural logarithm of the numerical value of AUC_(T).

The term “AUC_(∞)” (expressed in units of pg·h/mL) means AUC from time 0to infinity as extrapolated. The term “ln(AUC_(∞))” means the naturallogarithm of the numerical value of AUC_(∞).

The term “AUC_(T/∞)” (expressed in units of %) means the relativepercentage of AUC_(T) with respect to AUC_(∞).

The term “K_(el)” (expressed in units of hours⁻¹) means the apparentterminal rate constant, estimated by linear regression of the terminallinear portion of the log concentration versus time curve.

The term “T_(1/2el)” (expressed in units of hours) means the terminalhalf life, often assumed to be the half life of elimination.

The term “CL_(TOT)/F” (expressed in units of L/h) means the oralclearance, and is calculated as the dose divided by AUG_(∞) followingoral administration.

The term “V_(D)/F” (expressed in units of L) means the apparent volumeof distribution, and is calculated as the dose divided by the value of(K_(el)×AUC_(∞)) following oral administration.

The terms “voriconazole”, “fluconazole”, “cimetidine” and “propafenone”refer to the respective compounds known by those names in thepharmaceutical arts, as shown below.

Common Name and Trade Name(s) (and Source(s)) IUPAC Name ChemicalStructure Voriconazole VFEND ® (Pfizer) (2R,3S)-2-(2,4-difluorophenyl)-3-(5- fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Fluconazole Diflucan ®; Trican ® (Pfizer). 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1- yl)propan-2-ol

Cimetidine Tagamet ®; Tagamet HB ®; Tagamet HB200 ® (GlaxoSmithKline)2-cyano-1-methyl-3-(2-[(5- methyl-1H-imidazol-4-yl)methylthio]ethyl)guanidine

Propafenone Rythmol SR ® or Rytmonorm ® (Knoll; Abbott; ReliantPharmaceuticals) 1-{2-[2-hydroxy-3- (propylamino)propoxy]phenyl}-3-phenylpropan-1-one

As used herein with respect to drugs, the terms “extended-release” (ER,XR or XL), “timed-release” (TR), “sustained-release” (SR),“sustained-action” (SA), “controlled release” (CR), “modified-release”(MR) and “continuous-release” (Contin) refer to oral dosage forms(typically tablets or capsules) whose formulation and/or dosage form isdesigned to release the drug more slowly and steadily into thebloodstream over time than an immediate-release (IR) dosage form of thesame drug. As used herein with respect to drugs, the term“immediate-release” (IR) refers to a drug for which the formulation anddosage form are not designed to delay dissolution or absorption of thedrug into the body when orally administered.

When ranges are given by specifying the lower end of a range separatelyfrom the upper end of the range, it will be understood that the rangecan be defined by selectively combining any one of the lower endvariables with any one of the upper end variables that is mathematicallypossible.

Discussion

As discussed above, for several years the expert consensus has been thatthe removal of colchicine by CYP3A4 and P-gp is additive. I.e., it hasbeen believed that if either of CYP3A4 or P-gp is inhibited thencolchicine concentrations in the blood rise because the other has alimited capacity to increase its own rate of colchicine removal. Thisview has been reinforced by the observation that administration ofcolchicine is tolerated within only a narrow dosing window, even inpatients who have no ailment other than gout and who receive no drugother than colchicine.

The inventors have now discovered that single inhibitors of CYP3A4 andP-gp do not lead to greatly increased build-up of colchicine in thebody, unlike dual inhibitors, and do not necessitate a reduction incolchicine dose when coadministered with colchicine.

Therefore, in one embodiment the invention provides a method ofchronically treating a patient for an inflammatory disorder withcolchicine while concomitantly administering a second drug that is aninhibitor of CYP3A4 but is not an inhibitor for P-gp, wherein the methodcomprises: (a) administering to the patient a therapeutically effectivefixed maintenance dose of colchicine in an amount of from about 0.6 toabout 1.2 mg/day, for a maintenance period of a plurality of days; (b)before or after step (a), administering to the patient one or moretherapeutically effective doses of the second drug; and (c)concomitantly with step (b), administering to the patient the fixedmaintenance dose of colchicine of step (a) without dose reduction.

The CYP3A4 inhibitor can be a strong, moderate or weak inhibitor. Aparticularly suitable strong inhibitor is voriconazole. Voriconazole isa synthetic broad-spectrum antifungal agent available in scored whitetablets, each containing 200 mg voriconazole base for oraladministration. Voriconazole tablets are indicated for the treatment ofthe following systemic fungal infections: candidiasis, chronicmucocutaneous candidiasis, oral thrush, candiduria, blastomycosis,coccidioidomycosis, histoplasmosis, chromomycosis, andparacoccidioidomycosis. Voriconazole is a strong inhibitor of the CYP3A4isozyme. Co-administration of colchicine (being primarily metabolized bythe CYP3A4 enzyme) with a second drug such as voriconazole has beenthought by many to result in increased plasma concentrations ofcolchicine that could increase or prolong both therapeutic and adverseside effects. However typical maintenance dose ranges of about 200mg/day to about 400 mg/day of voriconazole may be safely coadministeredwith typical maintenance dose ranges of from about 0.6/day to about 1.2mg/day of colchicine.

A particularly suitable moderate inhibitor is fluconazole. Fluconazoleis a synthetic broad-spectrum antifungal agent available in scored whitetablets, each containing 200 mg fluconazole base for oraladministration. Fluconazole tablets are indicated for the treatment ofthe following systemic fungal infections: candidiasis, chronicmucocutaneous candidiasis, oral thrush, candiduria, blastomycosis,coccidioidomycosis, histoplasmosis, chromomycosis, andparacoccidioidomycosis. Fluconazole is a strong inhibitor of the CYP3A4isozyme. Co-administration of colchicine (being primarily metabolized bythe CYP3A4 enzyme) with a second drug such as fluconazole has beenthought by many to result in increased plasma concentrations ofcolchicine that could increase or prolong both therapeutic and adverseside effects. However typical maintenance dose ranges of about 200mg/day to about 400 mg/day of fluconazole may be safely coadministeredwith typical maintenance dose ranges of from about 0.6/day to about 1.2mg/day of colchicine.

A particularly preferred weak inhibitor is cimetidine. Cimetidine is asynthetic drug that inhibits stomach acid production. It is used totreat heartburn and peptic ulcers and is sold by Prestige Brands(formely by GlaxoSmithKline under the trade name Tagamet and variants ofthat name. Cimetidine has also been advocated for use to treat severaldermatological diseases. Common dosage regimes in adults include thefollowing: oral (800 mg to 1600 mg once a day at bedtime, or 300 mg fourtimes per day, with meals and at bedtime, or 400 mg twice daily, in themorning and at bedtime); and parenteral (300 mg IV or IM every 6 to 8hours, or a continuous IV infusion at a rate of 37.5 to 50 mg/hour, orup to a maximum rate of 100 mg/hour (2.4 g/day). For dyspepsia doses inpatients age 12 or over the dose is commonly 200 mg orally up to 30minutes before eating with no more than 2 doses per 24 hours. Pediatricdoses are commonly as follows: neonatal (5 to 10 mg/kg/day administeredIV or IM in divided doses every 8 to 12 hours), infant (10 to to 20mg/kg/day administered IV, IM, or oral in divided doses every 6 to 12hours); and children 20 to 40 mg/kg/day administered IV, IM, or oral individed doses every 6 hours). Cimetidine in a maintenance dose may besafely coadministered chronically with typical maintenance dose rangesof from about 0.6/day to about 1.2 mg/day of colchicine.

Another embodiment relates to the coadministration of colchicine withmolecules that are P-gp inhibitors but not CYP3A4 inhibitors. In thisembodiment the invention provides a method of chronically treating apatient for an inflammatory disorder while concomitantly administering asecond drug that is an inhibitor of P-gp but is not an inhibitor forCYP3A4, wherein the method comprises: (a) administering to the patient atherapeutically effective fixed maintenance dose of colchicine in anamount of from about 0.6 to about 1.2 mg/day, for a maintenance periodof a plurality of days; (b) before or after step (a), administering tothe patient one or more therapeutically effective doses of the seconddrug; and (c) concomitantly with step (b), administering to the patientthe fixed maintenance dose of colchicine of step (a) without dosereduction.

Propafenone is a particular P-gp inhibitor that does not inhibit CYP3A4for use in the invention. Propafenone is a synthetic drug that iscurrently sold by Reliant Pharmaceuticals under the brand names RythmolSR® and Rytmonorm®. It is an anti-arrhythmic medication for thetreatment of illnesses associated with rapid heart beats, e.g., atrialand ventricular arrhythmias. The dosage of propafenone variesconsiderably as a function of the clinical presentation of arrhythmia.About 900 mg/d is generally deemed the maximum safe dosage. Typicaltreatment begins with a high dosage (about 450-900 mg/d) and decreasesto a maintenance dose range of about 300 mg/d (e.g., a maintenance doserange of between 225 and 450 mg/day). Propafenone in a maintenance dosemay be safely coadministered chronically with typical maintenance doseranges of from about 0.6/day to about 1.2 mg/day of colchicine.

In either of the foregoing embodiments, the plurality of days in whichthe maintenance dose of colchicine is administered can extend 3, 7, 14,28, or even more days. In like manner, the P-gp inhibitor or CYP3A4inhibitor can be administered a single day or a second plurality ofdays, extending 2, 3, 5, 7, 10, 15 or more days.

In any of the foregoing embodiments, the colchicine is preferablyadministered orally, as in a capsule, tablet or oral suspension. Thesingle inhibitor can be administered via any route of administration,but is also preferably administered orally.

EXAMPLES

The invention may be further understood by consideration of thefollowing illustrative Examples. Example 1 is a comparative example ofprior art methods in which dual inhibitors of CYP3A4 and P-gp werecoadministered with colchicine and the pharmacokinetics of colchicineevaluated. Examples 2, 3, 4, 5 and 6 exemplify the present invention,and evaluate the pharmacokinetics of colchicine when single inhibitorsof CYP3A4 or P-gp are coadministered.

Example 1 Comparative Example for Dual Inhibitors

This Example summarizes the methods and data from R. A. Terkeltaub etal., “Novel evidence-based colchicine dose-reduction algorithm topredict and prevent colchicine toxicity in the presence of cytochromeP450 3A4/P-glycloprotein inhibitors,” Arthritis and Rheumatism, 2011;63:2226-2237, 3521 (erratum). To facilitate comparison with subsequentExamples of the present invention, Terkeltaub et al's empirical valuesare provided in the same units employed there and in a similar sequenceand format.

Drug-drug interaction trials were conducted with seven drugscoadministered with colchicine. Six of those drugs (cyclosporine,clarithromycin, ketoconazole, ritonavir, verapamil ER, and diltiazem ER)are dual inhibitors known to substantially inhibit both CYP3A4 and P-gp.The seventh tested drug (azithromycin) was at most marginal in bothfunctions: depending on the publication it is described as a weakinhibitor or non-inhibitor for CYP3A4 and also depending on thepublication it is described as an inhibitor or a non-inhibitor for P-gp.Each trial was an open-label, drug interaction study to investigate theeffects of multiple-dose dual inhibitors on single-dose pharmacokineticsof colchicine in healthy male volunteers. The trial was a single center,non-randomized, open-label, one-sequence, two period drug-druginteraction (DDI) study.

The diagnosis and main criteria of inclusion were: male and femalevolunteers from white, black or another race; non-smokers; at least18-45 years of age; with a body mass index of 18-32 kg/m² and noconcomitant use of medications or other products that might interferewith the interpretation of pharmacokinetic results from the studies.Subjects were in good health as determined by a medical history,physical examination, measurement of vital signs and clinical laboratorytesting.

The treatment protocols each included two colchicine administrationsseparated by a wash-out period so as to obtain representative bloodconcentration values with and without the presence of the second drug.Each study began with 24 subjects; some subjects withdrew but forreasons unrelated to adverse health effects.

-   -   Cyclosporine: colchicine (0.6 mg) was administered on days 1        (fasted state in the morning) and 15, and cyclosporine (100 mg        once) was administered on day 15. (23 subjects completed the        study).    -   Clarithromycin: colchicine (0.6 mg) was administered on days 1        (fasted state in the morning), 22 and 29, and clarithromycin 250        mg (administered twice daily) was administered on days 22-29.        (23 subjects completed the study).    -   Ketoconazole: colchicine (0.6 mg) was administered on days 1        (fasted state in the morning) and 19, and ketoconazole (200 mg        twice daily). (24 subjects completed the study).    -   Ritonavir: colchicine (0.6 mg) was administered on days 1        (fasted state in the morning) and 19, and ritonavir (100 mg        twice daily) was administered on days 15-19. (17 subjects        completed the study).    -   Verapamil ER: colchicine (0.6 mg) was administered on days 1        (fasted state in the morning) and 19, and verapamil ER (240 mg        once daily) was administered on days 15-19. (24 subjects        completed the study).    -   Diltiazem ER: colchicine (0.6 mg) was administered on days 1        (fasted state in the morning) and 21, and diltiazem ER (240 mg        once daily) was administered on days 15-21 (total of 7 doses).        (20 subjects completed the study).    -   Azithromycin: colchicine (0.6 mg) was administered on days 1        (fasted state in the morning) and 19, and azithromycin 500 mg        (2×250 mg) was administered on day 15, and 250 mg (once daily)        was administered on days 16-19. (21 subjects completed the        study).

The blood of the subjects was collected in 34 samples each as follows:for the colchicine administration on Day 1 (denoted here as Treatment-1)and on an end day (denoted here as Treatment-2) for colchicineadministration (i.e., after a wash-out period), a blood sample wascollected prior to and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36,48, 72 and 96 hours after colchicine administration.

The colchicine content of human plasma was analyzed by HPLC withLC/MS/MS detection and an assay range of 200-40,000 pg/mL.

Safety was evaluated through assessment of adverse events and othercriteria.

The pharmacokinetic (PK) parameters of these trials were (as stated inthe notation of the remaining Examples in the present application)C_(max), AUC_(T), AUC_(∞), T_(max), K_(el), T_(1/2el), Cl_(TOT)/F andVd/F. Statistical analysis of the pharmacokinetic parameters employedarithmetic means and were based on a 90% confidence interval of theratio of geometric means for the C_(max), AUC_(T), K_(el), T_(1/2el) andCl_(TOT)/F. Safety was determined by descriptive statistics.

A summary of the safety results follows in Table 1. The pharmacokineticparameters are summarized in Tables 2, 3, 4, 5, 6, 7 and 8 forcyclosporine, clarithromycin, ketoconazole, verapamil ER, diltiazem andazithromycin, respectively.

TABLE 1 Incidence of Adverse Effects for Colchicine when Coadministeredwith Various Inhibitors. Result Cyclo- Clarith- Ketoco- Ritona- Verap-Diltia- Azithro- Safety Criteria sporine romycin nazole vir amil ER zemER mycin Number of 24 6 14 10 5 14 14 11 subjects with (25.0%) (58.3)(41.7) (20.8) (58.3) (58.3) (45.8) adverse events overall Total numberof 5 26 11 8 22 21 27 adverse events Number of None None None None None1 1 subjects vomiting vomiting withdrawn for safety reasons

TABLE 2 Comparative Pharmacokinetics for Colchicine when Coadministeredwith Cyclosporine ARITHMETIC* or 90% ln-transformed GEOMETRIC**CONFIDENCE Cyclosporine MEANS RATIO LIMITS (%) PARAMETER TREATMENT-2TREATMENT-1 (%) LOWER UPPER C_(max) (pg/mL)** 8,820 2,720 324.17 292.32356.01 AUC_(T) (pg · h/mL)** 29,830 12,555 317.48 291.79 343.17 K_(el)(hours⁻¹)* 0.038 0.147 26.07 9.14 43 T_(1/2el) (hours)* 20.65 6.777104.43 88 120.85 CL_(TOT)/F (L/h) 13.42 48.24 27.82 14.78 40.87

TABLE 3 Comparative Pharmacokinetics for Colchicine when Coadministeredwith Clarithromycin ARITHMETIC* or 90% ln-transformed GEOMETRIC**CONFIDENCE Clarithromycin MEANS RATIO LIMITS (%) PARAMETER TREATMENT-2TREATMENT-1 (%) LOWER UPPER C_(max) (pg/mL)** 8,440 2,840 297.49 277.65317.33 AUC_(T) (pg · h/mL)** 41,950 12,370 339.21 314.64 363.78 K_(el)(hours⁻¹)* 0.0296 0.1324 22.35 5.28 39.43 T_(1/2el) (hours)* 30.31 8.89340.97 277.7 404.24 CL_(TOT)/F (L/h) 12.0 46.8 — — —

TABLE 4 Comparative Pharmacokinetics for Colchicine when Coadministeredwith Ketoconazole ARITHMETIC* or 90% ln-transformed GEOMETRIC**CONFIDENCE Ketoconazole MEANS RATIO LIMITS (%) PARAMETER TREATMENT-2TREATMENT-1 (%) LOWER UPPER C_(max) (pg/mL)** 5,270 2,780 189.52 176.37202.67 AUC_(T) (pg · h/mL)** 34,380 11,990 286.75 265.75 307.85 K_(el)(hours⁻¹)* 0.332 0.1491 22.29 8.05 36.52 T_(1/2el) (hours)* 26.06 6.28415.24 339.4 491.09 CL_(TOT)/F (L/h) 14.8 49.3 30.01 17.81 42.22

TABLE 5 Comparative Pharmacokinetics for Colchicine when Coadministeredwith Ritonavir ARITHMETIC* or 90% ln-transformed GEOMETRIC** CONFIDENCERitonavir MEANS RATIO LIMITS (%) PARAMETER TREATMENT-2 TREATMENT-1 (%)LOWER UPPER C_(max) (pg/mL)** 4,990 1,870 267.08 239.71 294.45 AUC_(T)(pg · h/mL)** 29,050 8,410 345.32 304.35 386.29 K_(el) (hours⁻¹)* 0.4880.1666 131.83 117.25 146.41 T_(1/2el) (hours)* 17.41 5.15 338.42 274.48402.36 CL_(TOT)/F (L/h) 18.59 67.93 27.37 13 41.74

TABLE 6 Comparative Pharmacokinetics for Colchicine when Coadministeredwith Verapamil ER ARITHMETIC* or 90% ln-transformed GEOMETRIC**CONFIDENCE Verapamil ER MEANS RATIO LIMITS (%) PARAMETER TREATMENT-2TREATMENT-1 (%) LOWER UPPER C_(max) (pg/mL)** 3,850 2,970 129.72 115.29149.88 AUC_(T) (pg · h/mL)** 24.64 13,090 199.29 174.69 201.88 K_(el)(hours⁻¹)* 0.0480 0.1409 34.05 20.13 47.96 T_(1/2el) (hours)* 17.17 4.3274.99 239.97 310.02 CL_(TOT)/F (L/h) 21.01 43.93 47.81 37.87 57.76

TABLE 7 Comparative Pharmacokinetics for Colchicine when Coadministeredwith Diltiazem ER ARITHMETIC* or 90% ln-transformed GEOMETRIC**CONFIDENCE Diltiazem ER MEANS RATIO LIMITS (%) PARAMETER TREATMENT-2TREATMENT-1 (%) LOWER UPPER C_(max) (pg/mL)** 2,800 2,170 129.03 108.22149.84 AUC_(T) (pg · h/mL)** 12,730 10,040 176.67 146.49 206.84 K_(el)(hours⁻¹)* 0.0838 0.1589 52.76 38.24 67.27 T_(1/2el) (hours)* 12.5 5.51226.66 176.7 276.63 CL_(TOT)/F (L/h) 34.7 58.88 58.94 45.81 72.06

TABLE 8 Comparative Pharmacokinetics for Colchicine when Coadministeredwith Azithromycin ARITHMETIC* or 90% ln-transformed GEOMETRIC**CONFIDENCE Azithromycin MEANS RATIO LIMITS (%) PARAMETER TREATMENT-2TREATMENT-1 (%) LOWER UPPER C_(max) (pg/mL)** 3,050 2,740 111.15 94.01128.99 AUC_(T) (pg · h/mL)** 17,160 11,980 143.3 124.85 161.75 K_(el)(hours⁻¹)* 0.1426 0.147 97.02 79.03 115 T_(1/2el) (hours)* 6.71 6.07110.44 79.82 141.02 CL_(TOT)/F (L/h) 35.01 50.24 69.69 57.58 81.8

Example 2 Clinical Conditions for Single Inhibitors of CYP3A4 or P-gp

The following experimental design was the template for studies reportedin Examples 3, 4, 5 and 6. Each investigation was a clinical trialconducted as a one-direction, open-label, drug interaction study toinvestigate the effects of multiple doses of inhibitors on single-dosepharmacokinetics of colchicine in 12 healthy male volunteers, all ofwhom completed each study except where noted. Each study was a singlecenter, non-randomized, open-label, one-sequence, crossover study.

The primary objective of each study was to investigate the effect ofmultiple doses of a potentially interacting drug on the pharmacokineticsof colchicine administered as a single 0.6-mg dose in healthy subjectsunder fasted conditions. The secondary objective was to assess thesafety and tolerability of a single 0.6-mg dose of colchicineadministered alone and in combination with multiple-doses of thepotentially interacting drug. The test product was a 0.6 mg oral capsuleof colchicine (West Ward Pharmaceutical Corp., USA).

Except where noted otherwise the diagnosis and main criteria forinclusion of subjects in each study were: male volunteers, non- orex-smokers, at least 18 years of age with a body mass index greater thanor equal to 18.50 and below 30.00 kg/m². Subjects were in good health asdetermined by a medical history, complete physical examination(including vital signs), electrocardiogram (ECG) and the usual clinicallaboratory tests (hematology, biochemistry, urinalysis) includingnegative HIV, Hepatitis B and Hepatitis C tests as well as negativescreening for ethanol and drugs of abuse in urine.

The treatment protocol included two colchicine administrations separatedby a wash-out of 8 calendar days, as follows, so as to obtainrepresentative blood concentration values with and without the presenceof the inhibitor.

-   -   Day 1 (Treatment-1): Single dose of 1×0.6 mg of colchicine was        orally administered under fasting conditions in the morning.    -   Days 4 to 8 (5 consecutive days): Single dose of inhibitor drug        was orally administered twice daily (once in the morning and        once in the evening, 12 hours apart).    -   Day 9 (Treatment-2): Single dose of 1×0.6 mg of colchicine and        single dose of inhibitor drug were orally administered        concomitantly under fasting conditions in the morning.        For pharmacokinetic analysis the blood of the subjects was        collected in 40 samples each as follows: on Days 1 and 9, a        blood sample was collected prior to and 0.25, 0.5, 0.75, 1,        1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 72        hours after colchicine administration. The colchicine content of        human plasma was then analyzed by HPLC with MS/MS detection with        an assay range of 20.0 pg/mL to 18,000.0 pg/mL (for voriconazole        and propafenone) or 20.0 pg/mL to 10,000.0 pg/mL (for        fluconazole and cimetidine).

The mathematical model and statistical methods of pharmacokineticparameters were the following: main absorption and dispositionparameters using a non-compartmental approach with a log-linear terminalphase assumption; trapezoidal rule to estimate area under the curve; andterminal phase estimation based on maximizing the coefficient ofdetermination. The pharmacokinetic parameters evaluated in this trialwere Cmax, AUC_(T), AUG_(∞), T_(max), AUC_(T/∞), K_(el), T_(1/2el),Cl_(TOT)/F and Vd/F. Statistical analysis was based on a parametricrandom ANOVA model of the pharmacokinetic parameters; two-sided 90%confidence interval of the ratio of geometric means for the C_(max),AUC_(T) and AUG_(∞) based on ln-transformed data. The ANOVA model wasbased on fixed factors and treatment.

Safety was evaluated through assessment of adverse events, standardlaboratory evaluations, physical examination (including vital signs) andECG. Safety was determined by descriptive statistics.

Example 3 Strong Inhibitor of CYP3A4; Non-Inhibitor for P-gp

A study was conducted according to the Example 2 using voriconazole asthe inhibitor. Voriconazole is a strong inhibitor of CYP3A4 but not aninhibitor of P-gp. The inhibitor dosage form was an oral 200 mgfilm-coated capsule of Vfend® (voriconazole, from Roerig, Division ofPfizer Inc., USA).

Voriconazole's safety for coadministration was found to be comparable toobservations in the absence of any coadministered drug. The relativeincidence of adverse effects coadministration with voriconazole issummarized in Table 9. The comparative plasma concentration results areshown graphically in FIG. 1 and FIG. 2.

TABLE 9 Incidence of Adverse Effects for Colchicine when Coadministeredwith Voriconazole. Safety Criteria Result Number of subjectsexperiencing adverse events 7 of 12 (58.3%) after Treatment-1 Totalnumber of adverse events after Treatment-1 20 Number of subjectsexperiencing adverse events 1 of 12 (8.3%)  after Treatment-2 Totalnumber of adverse events after Treatment-2  2 Relative severity ofadverse events Mild to moderate; None severe Number of serious adverseevents or deaths None Number of adverse events requiring medication Noneafter Treatment-1 Number of subjects withdrawn for safety reasons None

It was expected that a strong CYP3A4 inhibitor such as voriconazolewould increase the exposure of colchicine. However voriconazole hadlittle effect on colchicine's AUC, and decreased C_(max) by about 20%.Taking into consideration the extent of bioavailability, and the rangeof mean values for C_(max) and AUC, with and without co-administrationwith the interacting drug, no major difference in safety was observed:colchicine was generally safe and well tolerated by the subjects. Basedon the observed pharmacokinetic results colchicine's dosing regimen doesnot need to be adjusted with concomitant use of voriconazole. Thepharmacokinetic parameters for colchicine in this study follow in Tables10 and 11.

TABLE 10 Comparative Pharmacokinetics for Colchicine when Coadministeredwith Voriconazole TREATMENT-2 TREATMENT-1 PARAMETER MEAN C.V. (%) MEANC.V. (%) C_(max) (pg/mL) 2058.2 44.9 2662.6 49.8 ln (C_(max)) 7.5147 7.17.7420 7.9 T_(max) (median hours) 1.50 35.4 1.38 30.8 AUC_(T) (pg ·h/mL) 20730.8 36.9 19604.9 39.4 ln (AUC_(T)) 9.8783 3.7 9.7950 4.9AUC_(∞) (pg · h/mL) 24100.1 37.3 22357.6 40.3 ln (AUC_(∞)) 10.0285 3.69.9262 4.7 AUC_(T/∞) (%) 86.14 4.6 87.75 3.6 K_(el) (hours⁻¹) 0.022716.5 0.0240 15.8 T_(1/2el) (hours) 31.30 17.0 29.63 16.7 CL_(TOT)/F(L/h) 28.1 35.6 33.0 60.9 V_(D)/F (L) 1261.3 39.2 1345.1 49.6

TABLE 11 Pharmacokinetic Ranges and Ratios for Colchicine whenCoadministered with Voriconazole GEOMETRIC LSMEANS 90% INTRA- (pg/mL forC_(max); CONFIDENCE PARAM- SUBJECT pg · h/mL for AUC_(T) and AUC_(∞) ⁾RATIO LIMITS (%) ETER C.V. (%) TREATMENT-2 TREATMENT-1 (%) LOWER UPPERC_(max) 30.8 1834.9 2303.1 79.67 63.90 99.33 AUC_(T) 28.0 19502.617943.1 108.69 88.89 132.91 AUC_(∞) 27.2 22663.5 20459.6 110.77 91.06134.76

Example 4 Moderate Inhibitor of CYP3A4; Non-Inhibitor for P-gp

A study was conducted according to the protocol of Example 2, usingfluconazole as the inhibitor. Fluconazole is a moderate inhibitor ofCYP3A4 but not an inhibitor of P-gp. The inhibitor dosage form was anoral 200 mg tablet of Diflucan® (fluconazole, from Pfizer).

The fluconazole trial differed from the Example 2 protocol as follows.The subject inclusion criteria did not exclude smokers. And instead oftwice-daily doses (12 hours apart) of inhibitor drug on days 4 to 8,subjects instead received a double dose on the morning of day 4 (aloading dose) and a once-daily dose administered in the mornings of eachof days 5 to 8.

The safety of colchicine when coadministered with voriconazole wascomparable to observations in the absence of any coadministered drug.The relative incidence of adverse effects during coadministration withfluconazole is summarized in Table 12. The comparative plasmaconcentration results are shown graphically in FIG. 3 and FIG. 4.

TABLE 12 Incidence of Adverse Effects for Colchicine when Coadministeredwith Fluconazole Safety Criteria Result Number of subjects experiencingadverse events 3 of 12 (25.0%) after Treatment-1 Total number of adverseevents after Treatment-1 7 Number of subjects experiencing adverseevents 3 of 12 (25.0%) after Treatment-2 Total number of adverse eventsafter Treatment-2 3 Relative severity of adverse events Mild tomoderate; None severe Number of serious adverse events or deaths NoneNumber of adverse events requiring medication None after Treatment-1Number of subjects withdrawn for safety reasons None

As a moderate inhibitor of CYP3A4 fluconazole was expected tosignificantly increase the maximum concentration of colchicine in theblood. With co-administration of fluconazole the mean C_(max) forcolchicine increased by only 13%; overall exposure of colchicine (AUC)increased by somewhat more (40%). Taking into account the extent ofbioavailability, and the range of mean values for C_(max) and AUC, thesafety impact appears to be acceptable and no major difference in safetywas observed: colchicine was generally safe and well tolerated by thesubjects included in this study. Based on the observed pharmacokineticresults colchine's dosing regimen may remain unchanged with concomitantuse of fluconazole. The pharmacokinetic parameters for colchicine inthis study follow in Tables 13 and 14.

TABLE 13 Comparative Pharmacokinetics for Colchicine when Coadministeredwith Fluconazole TREATMENT-2 TREATMENT-1 PARAMETER MEAN C.V. (%) MEANC.V. (%) C_(max) (pg/mL) 2299.2 57.6 1925.6 34.6 ln (C_(max)) 7.6238 6.37.5020 5.0 T_(max) (median hours) 1.38 25.4 1.25 32.8 AUC_(T) (pg ·h/mL) 21270.7 33.6 14939.4 25.5 ln (AUC_(T)) 9.9215 3.0 9.5793 2.9AUC_(∞) (pg · h/mL) 25586.1 35.5 17477.7 24.7 ln (AUC_(∞)) 10.1018 3.19.7384 2.7 AUC_(T/∞) (%) 83.54 2.9 85.33 3.1 K_(el) (hours⁻¹) 0.020413.3 0.0206 11.6 T_(1/2el) (hours) 34.51 14.8 34.05 12.2 CL_(TOT)/F(L/h) 25.6 28.2 36.6 28.6 V_(D)/F (L) 1250.5 24.7 1807.7 32.1

TABLE 14 Pharmacokinetic Ranges and Ratios for Colchicine whenCoadministered with Fluconazole GEOMETRIC LSMEANS * 90% INTRA- (pg/mLfor C_(max) and CONFIDENCE PARAM- SUBJECT pg · h/mL for AUC_(T) andAUC_(∞)) RATIO LIMITS (%) ETER C.V. (%) TREATMENT-2 TREATMENT-1 (%)LOWER UPPER C_(max) 27.1 2046.3 1811.7 112.95 92.90 137.33 AUC_(T) 22.420364.2 14461.6 140.82 119.70 165.65 AUC_(∞) 22.5 24386.8 16955.6 143.83122.18 169.30

Example 5 Weak Inhibitor of CYP3A4; Non-Inhibitor for P-gp

A study was conducted according to the protocol of Example 2, usingcimetidine as the inhibitor. Cimetidine is a weak inhibitor of CYP3A4but not an inhibitor of P-gp. The inhibitor dosage form was an oral 800mg film-coated tablet USP of cimetidine (Mylan Pharmaceuticals Inc.,USA).

The cimetidine trial differed from the template protocol as follows. Thesubject inclusion criteria did not exclude females but did require thatthey test negative for pregnancy. And instead of twice-daily doses (12hours apart) of inhibitor drug on days 4 to 8, subjects instead receiveda double dose on the morning of day 4 (a loading dose) and a once-dailydose administered in the mornings of each of days 5 to 8.

Cimetidine's safety for coadministration was found to be comparable toobservations in the absence of any coadministered drug. The relativeincidence of adverse effects from coadministration with cimetidine issummarized in Table 15. The comparative plasma concentration results areshown graphically in FIG. 5 and FIG. 6.

TABLE 15 Incidence of Adverse Effects for Colchicine when Coadministeredwith Cimetidine. Safety Criteria Result Number of subjects experiencingadverse events after 7 of 12 (58.3%) Treatment-1 Total number of adverseevents after Treatment-1 11 Number of subjects experiencing adverseevents after 1 of 12 (8.3%)  Treatment-2 Total number of adverse eventsafter Treatment-2  2 Relative severity of adverse events Mild tomoderate; None severe Number of serious adverse events or deaths NoneNumber of adverse events requiring medication after None Treatment-1Number of subjects withdrawn for safety reasons None

It was expected that a weak CYP3A4 inhibitor such as cimetidine wouldhave a small effect on the exposure of colchicine. Unexpectedlycimetidine actually modestly decreased the peak plasma concentration ofcolchicine below levels observed without coadministration: colchicineC_(max) was lower by 33% and AUC was lower by 15%, though this was notsignificant.

Taking into consideration the extent of bioavailability, and the rangeof mean values for C_(max) and AUC, the safety impact appears to beacceptable and no major difference in safety would be expected with andwithout co-administration with cimetidine: colchicine was generally safeand well tolerated by the subjects included in this study. Based on theobserved pharmacokinetic results colchine's dosing regimen may remainunchanged with concomitant use of cimetidine. The pharmacokineticparameters for colchicine follow in Tables 16 and 17.

TABLE 16 Comparative Pharmacokinetics for Colchicine when Coadministeredwith Cimetidine TREATMENT-2 TREATMENT-1 PARAMETER MEAN C.V. (%) MEANC.V. (%) C_(max) (pg/mL) 2108.7 50.2 2996.8 38.6 ln (C_(max)) 7.5380 6.77.9318 5.3 T_(max) (median hours) 1.03 30.2 1.25 20.9 AUC_(T) (pg ·h/mL) 18082.1 41.6 20382.1 38.8 ln (AUC_(T)) 9.7243 4.3 9.8658 3.4AUC_(∞) (pg · h/mL) 21038.3 43.6 24000.7 39.2 ln (AUC_(∞)) 9.8696 4.410.0263 3.5 AUC_(T/∞) (%) 86.53 3.6 85.29 5.2 K_(el) (hours⁻¹) 0.022211.2 0.0201 16.9 T_(1/2el) (hours) 31.54 11.1 35.46 19.3 CL_(TOT)/F(L/h) 33.8 43.4 27.9 30.8 V_(D)/F (L) 1513.4 41.1 1410.8 31.3

TABLE 17 Pharmacokinetic Ranges and Ratios for Colchicine whenCoadministered with Cimetidine GEOMETRIC LSMEANS 90% INTRA- (pg/mL forC_(max) and CONFIDENCE PARAM- SUBJECT pg · h/mL for AUC_(T) and AUC_(∞))RATIO LIMITS (%) ETER C.V. (%) TREATMENT-2 TREATMENT-1 (%) LOWER UPPERC_(max) 29.3 1878.1 2784.5 67.45 54.65 83.25 AUC_(T) 18.7 16719.019260.8 86.80 75.78 99.43 AUC_(∞) 19.4 19334.3 22612.3 85.50 74.29 98.41

Example 6 Inhibitor of P-gp; Non-Inhibitor for CYP3A4

A study was conducted according to the protocol of Example 2, usingpropafenone as the inhibitor. Propafenone is an inhibitor of P-gp butnot of CYP3A4. The inhibitor dosage form was an oral 225 mg film-coatedtablet of Rythmol® (propafenone, from Halo Pharmaceutical Inc., USA forGlaxoSmithKline, USA).

The fluconazole trial differed from the Example 2 protocol as follows.Subjects were included only if they were not older than 45 years (asopposed to no upper limit). Also, in inclusion criteria the lowerthreshold for the body mass index was 21.00 (as opposed to 18.00) kg/m².Of the 12 subjects who began the study 3 dropped out for reasonsunrelated to the investigation.

Propafenone's safety for coadministration was found to be comparable toobservations in the absence of any coadministered drug. The relativeincidence of adverse effects when colchicine was coadministered withpropafenone is summarized in Table 18. The comparative plasmaconcentration results are shown graphically in FIG. 7 and FIG. 8.

TABLE 18 Incidence of Adverse Effects for Colchicine when Coadministeredwith Propafenone Safety Criteria Result Number of subjects experiencingadverse events after 9 of 12 (75.0%) Treatment-1 Total number of adverseevents after Treatment-1 19 Number of subjects experiencing adverseevents after 1 of 12 (8.3%)  Treatment-2 Total number of adverse eventsafter Treatment-2  1 Relative severity of adverse events Mild tomoderate; None severe Number of serious adverse events or deaths NoneNumber of adverse events requiring medication after None Treatment-1Number of subjects withdrawn for safety reasons None

It was expected that propafenone, being an inhibitor of colchicinetransport/export by P-gp would increase the exposure of colchicine. Butpropafenone had almost no effect on either colchicine's C_(max) or AUC:for C_(max) and AUC, an increase of only 7% and 1% respectively wasobserved. Taking into consideration the extent of bioavailability, andthe range of mean values for C_(max) and AUC, with and withoutco-administration with the interacting drug, no major difference insafety was observed: colchicine was generally safe and well tolerated bythe subjects. Based on the observed pharmacokinetic results colchicine'sdosing regimen does not need to be adjusted with concomitant use ofpropafenone. The pharmacokinetic parameters for colchicine follow inTables 19 and 20.

TABLE 19 Comparative Pharmacokinetics for Colchicine when Coadministeredwith Propafenone TREATMENT-2 TREATMENT-1 PARAMETER MEAN C.V. (%) MEANC.V. (%) C_(max) (pg/mL) 2206.0 17.3 2117.5 26.6 ln (C_(max)) 7.6861 2.27.6252 3.6 T_(max) (median hours) 1.00 39.5 1.50 23.0 AUC_(T) (pg ·h/mL) 16777.6 22.9 16626.1 21.8 ln (AUC_(T)) 9.7059 2.3 9.6956 2.4AUC_(∞) (pg · h/mL) 18864.3 24.3 18928.3 23.0 ln (AUC_(∞)) 9.8211 2.39.8221 2.6 AUC_(T/∞) (%) 89.16 3.4 88.21 5.0 K_(el) (hours⁻¹) 0.025013.6 0.0241 16.6 T_(1/2el) (hours) 28.25 15.4 29.74 21.5 CL_(TOT)/F(L/h) 33.3 20.9 33.5 27.7 V_(D)/F (L) 1359.0 28.1 1410.2 24.7

TABLE 20 Pharmacokinetic Ranges and Ratios for Colchicine whenCoadministered with Propafenone GEOMETRIC LSMEANS 90% INTRA- (pg/mL forC_(max) and CONFIDENCE PARAM- SUBJECT pg · h/mL for AUC_(T) and AUC_(∞))RATIO LIMITS (%) ETER C.V. (%) TREATMENT-2 TREATMENT-1 (%) LOWER UPPERC_(max) 23.0 2178.0 2049.3 106.28 87.07 129.73 AUC_(T) 20.5 16413.716245.3 101.04 84.57 120.71 AUC_(∞) 20.0 18418.2 18437.2 99.90 83.95118.87

In summary the present invention supports the safe use of conventionaldoses of colchicine in combination with conventional doses of a seconddrug that treats another medical condition but also inhibits one ofeither CYP3A4 or P-gp but not both. The present invention thus allowscolchicine to be dosed at safe and effective levels when coadministeredwith these drugs.

Those skilled in the art will appreciate that the present invention hasa wide range of applications and that it fulfills the needs of the priorart described herein and meets the above-stated objects. While there hasbeen shown and described preferred embodiments of the invention, it willbe evident to those skilled in the art that various modifications andchanges may be made thereto without departing from the spirit and thescope of the invention as set forth in the appended claims andequivalence thereof.

1-20. (canceled) 21) A method of treating a patient for an inflammatorydisorder, wherein the inflammatory disorder is chronic gout, familialMediterranean fever or Behcet's disease, with colchicine whileconcomitantly administering a second drug that is not an inhibitor ofthe cytochrome P450 3A4 isoenzyme (CYP3A4) but is an inhibitor ofP-glycoprotein 1 (P-gp), wherein the second drug is propafenone, whereinthe method comprises: a) administering to the patient a therapeuticallyeffective fixed maintenance dose of colchicine in an amount of fromabout 0.6 to about 1.2 mg/day, for a maintenance period of a pluralityof days, without administering propafenone; b) after step (a),administering to the patient one or more therapeutically effective dosesof propafenone; and c) concomitantly with step (b), administering to thepatient the fixed maintenance dose of colchicine of step (a) withoutdose reduction. 22) The method of claim 1, wherein propafenone isadministered at a dose of from 300 mg/day to 900 mg/day. 23) The methodof claim 1, wherein said fixed maintenance dose of colchicine is 0.6mg/day. 24) The method of claim 1, wherein said fixed maintenance doseof colchicine is 1.2 mg/day. 25) The method of claim 1, wherein theinflammatory disorder is chronic gout. 26) The method of claim 1,wherein said plurality of days comprises at least 7 days. 27) The methodof claim 1, wherein said fixed maintenance dose of colchicine is 0.6mg/day, and said inflammatory disorder is chronic gout. 28) A method oftreating a patient for an inflammatory disorder, wherein theinflammatory disorder is chronic gout, familial Mediterranean fever orBehçet's disease, by administering colchicine while concomitantlyadministering an inhibitor of P-glycoprotein 1 (P-gp) that is not aninhibitor of the cytochrome P450 3A4 isoenzyme (CYP3A4), wherein theinhibitor of P-gp is propafenone, wherein the method comprises: a)administering to the patient a plurality of therapeutically effectivedoses of propafenone for a plurality of days without administeringcolchicine; b) after step (a), administering to the patient one or morefixed maintenance doses of colchicine in an amount from about 0.6 toabout 1.2 mg/day; c) concomitantly with step (b) administering to thepatient a plurality of effective doses of propafenone; d) after step(c), discontinuing administration of propafenone and continuing toadminister the fixed maintenance doses of colchicine administered instep (b) without dose adjustment. 29) The method of claim 8, whereinsaid fixed maintenance dose of colchicine is 0.6 mg/day, and saidinflammatory disorder is chronic gout. 30) The method of claim 8,wherein said fixed maintenance dose of colchicine is 0.6 mg/day, saidinflammatory disorder is chronic gout, and said propafenone isadministered at a dose of from 300 mg/day to 900 mg/day. 31) The methodof claim 8, wherein said fixed maintenance dose of colchicine is 1.2mg/day, and said inflammatory disorder is chronic gout. 32) The methodof claim 8, wherein said fixed maintenance dose of colchicine is 1.2mg/day, said inflammatory disorder is chronic gout, and said propafenoneis administered at a dose of from 300 mg/day to 900 mg/day.